SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH.

PHS serves a similar role to SQS in plants and bacteria, catalyzing the synthesis of phytoene, a precursor of carotenoid compounds.

[8][9] The reaction mechanism of SQS requires a divalent cation, often Mg2+, to facilitate binding of the pyrophosphate groups on FPP.

[10] In the first half-reaction, two identical molecules of farnesyl pyrophosphate (FPP) are bound to squalene synthase (SQS) in a sequential manner.

[11] Starting at the top of the catalytic cycle below, the reaction begins with the ionization of FPP to generate an allylic carbocation.

A tyrosine residue (Tyr-171) plays a critical role in this step by serving as a proton donor to facilitate abstraction of pyrophosphate.

The phenolate anion generated previously then serves as a base to abstract a proton from this adduct to form a cyclopropane product, presqualene pyrophosphate (PSPP).

[5][10] The importance of a tyrosine residue in this process was demonstrated by mutagenesis studies with rat SQS (rSQS),[7] and by the fact that Tyr-171 is conserved in all known SQSs (and PHSs).

Keeping PSPP in the central channel of SQS is thought to protect the reactive intermediate from reacting with water.

This resulting carbocation is then ring-opened by a hydride delivered by NADPH, giving squalene, which is then released by SQS into the membrane of the endoplasmic reticulum.

The stereochemistry of the intermediates and the olefin geometry in the final product is dictated by the suprafacial nature of the 1,2-shifts and stereoelectronic requirements.

High levels of LDL-derived cholesterol inhibit HMG-CoA reductase activity significantly, since mevalonate is no longer needed for sterol production.

However, residual HMG-CoA reductase activity is observed even with very high LDL levels, such that FPP can be made for forming non-sterol products essential for cell growth.

This is since HMG-CoA reductase is the more significant control factor for regulating cholesterol synthesis (its activity is 98% inhibited when LDL levels are high).

[24] Therefore, inhibitors of SQS are of great interest in the treatment of hypercholesterolemia and prevention of coronary heart disease (CHD).

[28] Squalene synthase inhibitors that have been investigated for use in the prevention of cardiovascular disease include lapaquistat (TAK-475), zaragozic acid, and RPR 107393.